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Pharmacokinetics and Pharmacodynamics of Anti-Cancer Regimens: Emphasis on Busulphan and the Combination Therapies Epirubicin-Docetaxel and Fluorouracil-Epirubicin-Cyclophosphamide
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Although the main reason for the lack of distinct dose-response and -toxicity relationships for anti-cancer agents is due to variability in pharmacodynamics, variability in pharmacokinetics may also contribute. Hence, not only describing and quantifying the relationship between pharmacokinetics and dose-limiting toxicities, but characterising the pharmacokinetics and its associated variability are of obvious importance in the process of developing dosing strategies for anti-cancer regimens. The aim of this thesis was to characterize the pharmacokinetics of fluorouracil (5-FU), epirubicin (EPI), 4-hydroxycyclophosphamide (4-OHCP), docetaxel (DTX) and busulphan (Bu) and, additionally, the relationship between the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide and epirubicin-docetaxel regimens.

The pharmacokinetics of the combination EPI-DTX (ED) was studied in rats and patients, whereas the pharmacokinetics of Bu and 5-FU-EPI-4-OHCP (FEC) and haematological toxicity of the FEC and ED regimens was studied in patients only. All data analysis was performed using the NONMEM program.

For all studied drugs, except 4-OHCP, course-to-course variability was found to be less than the inter-individual variability in the pharmacokinetic parameters and thereby therapeutic drug monitoring (TDM) may be a suitable approach for dose individualisation of all studied drugs, except CP. The development of haematological toxicity after treatment was described well by a semi-physiological model. In the case of the ED regimen, the model appeared to be able to estimate the respective contribution of EPI and DTX to the bone marrow toxicity. Thus, using the final PK-PD model in the individualisation process may further improve the probability of prescribing the most appropriate dose regimen for a patient early in the treatment period. A dosing program was constructed by implementing the final Bu population model into Excel, which resulted in a flexible and easy to use dosing tool. Similar programs may be constructed and used for dose individualisation of other anti-cancer drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , 60 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 265
Keyword [en]
Pharmaceutical biosciences
Keyword [sv]
Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
URN: urn:nbn:se:uu:diva-1627ISBN: 91-554-5220-5OAI: oai:DiVA.org:uu-1627DiVA: diva2:161224
Public defence
2002-02-01, Lecture hall B42, Uppsala Biomedical Center, Uppsala, 13:15
Available from: 2002-01-11 Created: 2002-01-11Bibliographically approved

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